Heparin and related heparan sulfate glycosaminoglycans inhibit smooth muscle cell (SMC) proliferation and migration. This observation is of significance because heparan sulfate proteoglycans may play a role in regulating the growth state of SMCs in the normal arterial wall. Heparin inhibits SMC activation by thrombin and serum but not PDGF-BB. In preliminary experiments, we have shown that thrombin signaling is mediated in part by heparin-binding EGF-like growth factor (HB-EGF), activation of the EGF receptor (EGFR), and is not blocked by heparin. The primary objective of this research program is to test three hypotheses: 1. EGFR activation is required for SMC migration in vitro and in vivo; 2. PDGF-BB and thrombin utilize different mechanisms for EGFR transactivation; 3. EGFR activation induces the expression of heparan sulfate proteoglycans that then modulate EGFR function. We propose a combined in vitro and in vivo approach using cultured baboon and rat SMCs, the balloon-injured rat carotid artery, and pharmacological strategies for modulating HB-EGF, EGFR, PDGFR, and thrombin receptor function.